Mitochondrial dysfunction in paracetamol hepatotoxicity: in vitro studies in isolated mouse hepatocytes.
The effect of paracetamol intoxication on mitochondrial function was studied in isolated mouse hepatocytes. Inhibition of cellular respiration as well as a lowering of cellular ATP contents and ATP/ADP ratios was associated with exposure to toxic concentrations of paracetamol. Significantly, inhibition of 3-hydroxybutyrate- and lactate/pyruvate-supported respiration, as well as the reduction in cellular ATP levels and ATP/ADP ratios, preceded the appearance of plasma membrane damage, as assessed by LDH leakage. N-Acetylcysteine reduced the extent of plasma membrane damage induced by paracetamol and protected against the impairment of cellular respiration. This suggests that respiratory dysfunction was a consequence of the oxidation of paracetamol to its reactive metabolite within the liver cell. These findings indicate that paracetamol toxicity results in an impairment of mitochondrial function which precedes the loss of plasma membrane integrity.
Burcham
P C
PC
Department of Pharmacology, Queen Elizabeth II Medical Centre, University of Western Australia, Nedlands.
Harman
A W
AW
D000082:Acetaminophen / Q000633:toxicity*; D000111:Acetylcysteine / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000032:analysis; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005978:Glutathione / Q000032:analysis; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008099:Liver / Q000166:cytology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects
D000082:Acetaminophen; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D000111:Acetylcysteine